The goal of this project is to use a combination of genefically engineered mice and virus-mediated gene transfer in conjuncfion with mouse behavioral tests of learning and memory to identify the neural circuits that may underlie the cognifive decline in PD pafients. We will develop two novel transgenic mouse lines that will allow us either to block genefically the producfion of dopamine in discrete dopaminergic projecfion regions by viral-mediated recombination of the tyrosine hydroxylase gene or to ablate completely dopamine neurons. We will determine whether the loss of dopamine signaling (by inacfivafion of tyrosine hydroxylase) or dopamine neuron death (by action pf diphtheria toxin) leads to cognitive impairment and morphological changes within the striatum and/or prefrontal cortex (in conjuncfion with project 2). RELEVANCE (See instructions): Parkinson's disease (PD) is caused by dopamine neuron cell death, but it is unclear if PD-related cognifive impairment is due to the loss of dopamine signaling, or to the secondary effects of dopamine neuron degenerafion. We will develop 2 novel mouse models of PD to distinguish between the effects of loss of dopamine signaling and dopamine neuron degeneration on cognifive abilities.